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1. Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States

Author

Mondher Toumi, Jack Wallace, Chari Cohen, Chris Marshall, Helen Kitchen, Jake Macey, Hannah Pegram, Ashley F. Slagle, Robert G. Gish, Qin Ning, Hiroshi Yatsuhashi, Markus Cornberg, Maurizia Brunetto, Florian van Bömmel, Qing Xie, Dee Lee, Noriyuki Habuka, Urbano Sbarigia, Maria Beumont-Mauviel, Angelina Villasis Keever, Yasushi Takahashi, Yiwei Lu, Ao Liu, Qiaoqiao Chen, Tetsuro Ito, Olaf Radunz, Anna Puggina, Gudrun Hilgard, Eric K.H. Chan, and Su Wang

Subjects
Hepatitis B virus, Chronic Hepatitis B, Functional cure, Qualitative research, Self-stigma, Social impact, Public aspects of medicine, RA1-1270
Abstract

Abstract Background People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. Methods Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. Results Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. Conclusions CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

Published
2024
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2. Serum Mac-2 binding protein glycosylation isomer and galectin-3 levels in adult-onset Still’s disease and their association with cytokines

Author

Shuhei Yoshida, Tomohiro Koga, Yuya Fujita, Hiroshi Yatsuhashi, Haruki Matsumoto, Yuya Sumichika, Kenji Saito, Shuzo Sato, Tomoyuki Asano, Masao Kobayakawa, Hiromasa Ohira, Masashi Mizokami, Masaya Sugiyama, and Kiyoshi Migita

Subjects
adult-onset Still’s disease, cytokine, galectin-3, Mac-2 binding protein glycosylation isomer, interleukin-18, macrophage activation syndrome, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundAutoinflammation with cytokine dysregulation may be implicated in the pathophysiology of adult-onset Still’s disease (AOSD); however, the relationship between galectins and cytokines in patients with active AOSD remains unknown. We aimed to examine the relationship between circulating cytokines/chemokines and galectin-3 (Gal-3) or its ligand, Mac-2 binding protein glycosylation isomer (M2BPGi), in Japanese patients with AOSD.MethodsWe recruited 44 consecutive patients diagnosed with AOSD according to the Yamaguchi criteria, 50 patients with rheumatoid arthritis (RA) as disease controls, and 27 healthy participants. Serum M2BPGi levels were directly measured using a HISCL M2BPGi reagent kit and an automatic immunoanalyzer (HISCL-5000). Serum Gal-3 concentrations were measured by enzyme-linked immunosorbent assay. The serum levels of 69 cytokines were analyzed in patients with AOSD using a multi-suspension cytokine array. We performed a cluster analysis of each cytokine expressed in patients with AOSD to identify specific molecular networks.ResultsSignificant increases in the serum concentrations of Gal-3 and M2BPGi were found in the serum of patients with AOSD compared with patients with RA and healthy participants (both p

Published
2024
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3. Health state utilities of patients with hepatitis B and C and hepatitis-related conditions in Japan

Author

Hiroki Sugimori, Maki Hirao, Ataru Igarashi, Hiroshi Yatsuhashi, Shunya Ikeda, Naohiko Masaki, Hiroshi Yotsuyanagi, Takeshi Yoda, Takeshi Odajima, Tomoyuki Takura, and Tomohiro Hirao

Subjects
Medicine, Science
Abstract

Abstract Health state utilities are global measurements of quality of life and have been used to evaluate health outcomes for the cost-utility analysis. This study aimed to estimate the health state utilities of patients with hepatitis B (HB), hepatitis C (HC), and hepatitis-related diseases in Japan. We distributed a self-administered questionnaire, including the EuroQol 5-Dimension 5-Level (EQ-5D-5L), to 9,952 outpatients with several clinical conditions caused by HB or HC virus infection (such as asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis) and estimated the condition-specific utilities of patients with HB or HC. In patients with more severe conditions (patients with acute hepatitis, fulminant hepatitis, and hepatocellular carcinoma and patients undergoing post-liver transplantation), the utilities of these severe conditions were estimated by three hepatitis experts using the EQ-5D-5L. The means of the utilities for acute hepatitis, fulminant hepatitis, asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, compensated cirrhosis, hepatocellular carcinoma stage I/II, hepatocellular carcinoma stage III/IV, and post-liver transplantation were 0.529, − 0.111, 0.904, 0.868, 0.845, 0.722, 0,675, 0,428, and 0.651 and 0.876, 0.821, 0.737, 0.671, 0.675, 0.428, and 0.651 in HB and HC, respectively. To the best of our knowledge, this is the first study that comprehensively assessed the health state utilities of patients with HB, HC and hepatitis-related conditions from a nationwide survey in Japan using the EQ-5D-5L.

Published
2022
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4. Inhibition of CBP/β‐catenin signaling ameliorated fibrosis in cholestatic liver disease

Author

Masamichi Kimura, Koji Nishikawa, Yosuke Osawa, Jun Imamura, Kenzaburo Yamaji, Kenichi Harada, Hiroshi Yatsuhashi, Kazumoto Murata, Kouichi Miura, Atsushi Tanaka, Tatsuya Kanto, Michinori Kohara, Terumi Kamisawa, and Kiminori Kimura

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Chronic cholestatic liver diseases are characterized by injury of the bile ducts and hepatocytes caused by accumulated bile acids (BAs) and inflammation. Wnt/β‐catenin signaling is implicated in organ fibrosis; however, its role in cholestatic liver fibrosis remains unclear. Therefore, we explored the effect of a selective cAMP response element‐binding protein‐binding protein (CBP)/β‐catenin inhibitor, PRI‐724, on murine cholestatic liver fibrosis. PRI‐724 suppressed liver fibrosis induced by multidrug resistance protein 2 knockout (KO), bile duct ligation, or a 3.5‐diethoxycarbonyl‐1.4‐dihydrocollidine (DDC) diet; it also suppressed BA synthesis and macrophage infiltration. The expression of early growth response‐1 (Egr‐1), which plays a key role in BA synthesis, was increased in the hepatocytes of patients with cholestatic liver disease. PRI‐724 inhibited Egr‐1 expression induced by cholestasis, and adenoviral shEgr‐1‐mediated Egr‐1 knockdown suppressed BA synthesis and fibrosis in DDC diet–fed mice, suggesting that PRI‐724 exerts its effects, at least in part, by suppressing Egr‐1 expression in hepatocytes. Hepatocyte‐specific CBP KO in mice suppressed BA synthesis, liver injury, and fibrosis, whereas hepatocyte‐specific KO of P300, a CBP homolog, exacerbated DDC‐induced fibrosis. Intrahepatic Egr‐1 expression was also decreased in hepatocyte‐specific CBP‐KO mice and increased in P300‐KO mice, indicating that Egr‐1 is located downstream of CBP/β‐catenin signaling. Conclusion: PRI‐724 inhibits cholestatic liver injury and fibrosis by inhibiting BA synthesis in hepatocytes. These results highlight the therapeutic effect of CBP/β‐catenin inhibition in cholestatic liver diseases.

Published
2022
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5. Trends in hepatocellular carcinoma incident cases in Japan between 1996 and 2019

Author

Masahito Nakano, Hiroshi Yatsuhashi, Shigemune Bekki, Yuko Takami, Yasuhito Tanaka, Yoko Yoshimaru, Koichi Honda, Yasuji Komorizono, Masaru Harada, Michihiko Shibata, Shotaro Sakisaka, Satoshi Shakado, Kenji Nagata, Tomoharu Yoshizumi, Shinji Itoh, Tetsuro Sohda, Satoshi Oeda, Kazuhiko Nakao, Ryu Sasaki, Tsutomu Yamashita, Akio Ido, Seiichi Mawatari, Makoto Nakamuta, Yoshifusa Aratake, Shuichi Matsumoto, Tatsuji Maeshiro, Takashi Goto, and Takuji Torimura

Subjects
Medicine, Science
Abstract

Abstract We examined the epidemiological trends, including the distribution of sex, age, and disease etiology, in HCC incident cases, over 24 years. Data of 20,547 HCC patients (1996–2019) were analyzed in this prospective study. We divided the study period into four 6-yearly quarters. HCC etiology was categorized as hepatitis B virus (HBV) infection, HBV + hepatitis C virus (HCV) infection, HCV infection, and both negative (non-BC). The incident cases of HCC per quarter of the study period were 4311 (21.0%), 5505 (26.8%), 5776 (28.1%), and 4955 (24.1%), sequentially. Overall, 14,020 (68.2%) patients were male. The number of HCC cases in patients

Published
2022
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6. Switching from entecavir to tenofovir disoproxil fumarate for HBeAg-positive chronic hepatitis B patients: a phase 4, prospective study

Author

Fumitaka Suzuki, Yoshiyuki Suzuki, Yoshiyasu Karino, Yasuhito Tanaka, Masayuki Kurosaki, Hiroshi Yatsuhashi, Tomofumi Atarashi, Masanori Atsukawa, Tsunamasa Watanabe, Masaru Enomoto, Masatoshi Kudo, Naoto Maeda, Hiroshi Kohno, Kouji Joko, Kojiro Michitaka, Koichiro Miki, Kazuhiro Takahashi, Tatsuya Ide, Shigetoshi Fujiyama, Tomoko Kohno, Hiroshi Itoh, Sakiyo Tsukamoto, Yuko Suzuki, Yoshiaki Kawano, Wataru Sugiura, and Hiromitsu Kumada

Subjects
Tenofovir disoproxil fumarate, Chronic hepatitis B, HBsAg, HBeAg-positive, Entecavir, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Background Tenofovir disoproxil fumarate (TDF) is widely used and recommended as first-line treatment for patients infected with the hepatitis B virus (HBV). However, current data are limited regarding the efficacy and safety of switching to TDF for the treatment of chronic hepatitis B in hepatitis B e-antigen (HBeAg)-positive patients who are virologically suppressed with another nucleos(t)ide analogue. The primary objective of this study was to evaluate the hepatitis B surface antigen (HBsAg) reduction potential of switching from entecavir (ETV) to TDF at week 48 in HBeAg-positive chronic hepatitis B patients with undetectable serum HBV-DNA. Methods In this multicenter, single-arm, open-label, phase 4 clinical study, 75 participants currently treated with ETV 0.5 mg once daily were switched to TDF 300 mg once daily for 96 weeks. Results At week 48, 3/74 participants (4%) achieved 0.25 log10 reduction of HBsAg levels from baseline (the primary endpoint). Mean HBsAg reduction was −0.14 log10 IU/mL and 12% (9/74) achieved 0.25 log10 reduction by 96 weeks. No participants achieved HBsAg seroclearance. HBsAg reduction at weeks 48 and 96 was numerically greater in participants with higher alanine aminotransferase levels (≥ 60 U/L). Seventeen participants (25%) achieved HBeAg seroclearance up to week 96. No participants experienced viral breakthrough. All drug-related adverse events (18 participants [24%]) were mild in intensity, including an increase in urine beta-2-microglobulin (15 participants [20%]). Conclusions In conclusion, HBsAg reduction was limited after switching from ETV to TDF in this study population. Further investigation is warranted to better understand the clinical impact of switching from ETV to TDF. ClinicalTrials.gov: NCT03258710 registered August 21, 2017. https://clinicaltrials.gov/ct2/show/NCT03258710?term=NCT03258710&draw=2&rank=1

Published
2021
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7. Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study

Author

Eiichi Ogawa, Atsushi Tanaka, Kenichi Harada, Hiroshi Yatsuhashi, Kazumoto Murata, Masamichi Kimura, Jun Imamura, Masanao Saio, Yoshihiro Ikura, Kouichi Miura, Ichiro Ieiri, and Kiminori Kimura

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Objective This study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/β-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC).Design An open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score.Results Seven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis.Conclusion Administration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted.Trial registration number NCT04047160.

Published
2022
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8. Albumin platelet product as a novel score for liver fibrosis stage and prognosis

Author

Koji Fujita, Kazumi Yamasaki, Asahiro Morishita, Tingting Shi, Joji Tani, Noriko Nishiyama, Hideki Kobara, Takashi Himoto, Hiroshi Yatsuhashi, and Tsutomu Masaki

Subjects
Medicine, Science
Abstract

Abstract Fibrosis-4 index, a conventional biomarker for liver fibrosis stage, is confounded by age and hepatitis activity grade. The current retrospective multicenter study aimed to formulate the novel indices of liver fibrosis by mathematically combining items of peripheral blood examination and to evaluate ability of prognosis prediction. After a novel index was established in a training cohort, the index was tested in a validation cohort. Briefly, a total of 426 patients were enrolled in a training cohort. Albumin and platelet most strongly correlated to fibrosis stage among blood examination. Albumin platelet product (APP) = Albumin × platelet/1000 could differentiate the four stages of liver fibrosis (p

Published
2021
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9. Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines

Author

Nao Nishida, Masaya Sugiyama, Jun Ohashi, Yosuke Kawai, Seik-Soon Khor, Sohji Nishina, Kazumi Yamasaki, Hirohisa Yazaki, Kaori Okudera, Akihiro Tamori, Yuichiro Eguchi, Aiko Sakai, Keisuke Kakisaka, Hiromi Sawai, Takayo Tsuchiura, Miyuki Ishikawa, Keisuke Hino, Ryo Sumazaki, Yasuhiro Takikawa, Tatsuo Kanda, Osamu Yokosuka, Hiroshi Yatsuhashi, Katsushi Tokunaga, and Masashi Mizokami

Subjects
Medicine, Science
Abstract

Abstract Hepatitis B (HB) vaccines (Heptavax-II and Bimmugen) designed based on HBV genotypes A and C are mainly used for vaccination against HB in Japan. To determine whether there are differences in the genetic background associated with vaccine responsiveness, genome-wide association studies were performed on 555 Heptavax-II and 1193 Bimmugen recipients. Further HLA imputation and detailed analysis of the association with HLA genes showed that two haplotypes, DRB1*13:02-DQB1*06:04 and DRB1*04:05-DQB1*04:01, were significantly associated in comparison with high-responders (HBsAb > 100 mIU/mL) for the two HB vaccines. In particular, HLA-DRB1*13:02-DQB1*06:04 haplotype is of great interest in the sense that it could only be detected by direct analysis of the high-responders in vaccination with Heptavax-II or Bimmugen. Compared with healthy controls, DRB1*13:02-DQB1*06:04 was significantly less frequent in high-responders when vaccinated with Heptavax-II, indicating that high antibody titers were less likely to be obtained with Heptavax-II. As Bimmugen and Heptavax-II tended to have high and low vaccine responses to DRB1*13:02, 15 residues were found in the Heptavax-II-derived antigenic peptide predicted to have the most unstable HLA-peptide binding. Further functional analysis of selected hepatitis B patients with HLA haplotypes identified in this study is expected to lead to an understanding of the mechanisms underlying liver disease.

Published
2021
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10. Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response

Author

Takashi Higuchi, Shomi Oka, Hiroshi Furukawa, Shigeto Tohma, Hiroshi Yatsuhashi, and Kiyoshi Migita

Subjects
Autoimmune hepatitis, Genetic risk factor, HLA, Single nucleotide variant, Liver cirrhosis, Medicine, Genetics, QH426-470
Abstract

Abstract Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.

Published
2021
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11. JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells

Author

Yuya Fujita, Naoki Matsuoka, Jumpei Temmoku, Makiko Furuya-Yashiro, Tomoyuki Asano, Shuzo Sato, Haruki Matsumoto, Hiroshi Watanabe, Hideko Kozuru, Hiroshi Yatsuhashi, Atsushi Kawakami, and Kiyoshi Migita

Subjects
Baricitinib, GM-CSF, IL-1β, Janus kinases, Rheumatoid arthritis, Tofacitinib, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines. Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA. However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors. We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells. Results Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400 nM) in THP-1 cells. Whereas compared with baricitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations (≤ 100 nM). All JAKi inhibited GM-CSF-induced IL-1β production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1β production were larger compared to those of tofacitinib or upadacitinib at lower concentrations (≤ 100 nM). Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils. Conclusion We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells. Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi in the inhibition of JAK2 signaling pathways.

Published
2020
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12. Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Author

Kazuko Ueno, Yoshihiro Aiba, Yuki Hitomi, Shinji Shimoda, Hitomi Nakamura, Olivier Gervais, Yosuke Kawai, Minae Kawashima, Nao Nishida, Seik‐Soon Kohn, Kaname Kojima, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ohta, Takuya Komura, Satoru Tsuruta, Kazuhiko Yamauchi, Tatsuro Kobata, Amane Kitasato, Tamotsu Kuroki, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Kiyoshi Migita, Hiromasa Ohira, Atsushi Tanaka, Hajime Takikawa, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura, and PBC‐GWAS Consortium in Japan

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Genome‐wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease‐susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single‐nucleotide polymorphisms (P 2 versus controls (P

Published
2020
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13. Hydroxychloroquine inhibits IL-1β production from amyloid-stimulated human neutrophils

Author

Yuya Fujita, Naoki Matsuoka, Jumpei Temmoku, Makiko Yashiro Furuya, Tomoyuki Asano, Shuzo Sato, Hiroko Kobayashi, Hiroshi Watanabe, Eiji Suzuki, Takeshi Urano, Hideko Kozuru, Hiroshi Yatsuhashi, Tomohiro Koga, Atsushi Kawakami, and Kiyoshi Migita

Subjects
Amyloid, Hydroxychloroquine, Inflammasome, Interleukin-1 beta, Neutrophils, NLR family pyrin domain containing 3, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background Hydroxychloroquine (HCQ) is used for the treatment of patients with rheumatic diseases. We tested the hypothesis that HCQ affects the NLRP3 inflammasome, which is involved in autoinflammation. Methods Human neutrophils were stimulated with serum amyloid A (SAA) in vitro and measured for IL-1β and caspase-1 (p20) secretion by ELISA. Pro-IL-1β mRNA expression in human neutrophils was quantified by real-time RT-PCR. Results SAA stimulation induced significant production of IL-1β in human neutrophils. SAA stimulation also induced NF-κB activation, pro-IL-1β mRNA expression, and NLRP3 protein expression in human neutrophils. HCQ pretreatment significantly inhibited the SAA-induced IL-1β production in human neutrophils, but did not affect the SAA-induced NF-κB activation, pro-IL-1β mRNA expression, and NLRP3 protein expression. Furthermore, SAA stimulation induced cleaved caspase-1 (p20) secretion from human neutrophils, and this release was suppressed by HCQ pretreatment. Conclusions Treatment with HCQ was associated with impaired production of IL-1β in SAA-stimulated human neutrophils without affecting the priming process of the NLRP3 inflammasome such as pro-IL-1β or NLRP3 induction. These findings suggest that HCQ affects the NLRP3 activation process, resulting in the impaired IL-1β production in human neutrophils, as representative innate immune cells.

Published
2019
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14. Predictors of hepatocellular carcinoma recurrence associated with the use of direct‐acting antiviral agent therapy for hepatitis C virus after curative treatment: A prospective multicenter cohort study

Author

Masahito Nakano, Hironori Koga, Tatsuya Ide, Ryoko Kuromatsu, Satoru Hashimoto, Hiroshi Yatsuhashi, Masataka Seike, Nobito Higuchi, Makoto Nakamuta, Satoshi Shakado, Shotaro Sakisaka, Satoshi Miuma, Kazuhiko Nakao, Yoko Yoshimaru, Yutaka Sasaki, Satoshi Oeda, Yuichiro Eguchi, Yuichi Honma, Masaru Harada, Kenji Nagata, Seiichi Mawatari, Akio Ido, Tatsuji Maeshiro, Shuichi Matsumoto, Yuko Takami, Tetsuo Sohda, and Takuji Torimura

Subjects
DAA, HCV, hepatocarcinogenesis, liver cancer, SVR, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Previous studies have suggested an association between the use of direct‐acting antiviral agents (DAAs) for treating hepatitis C virus (HCV) infection and the resulting decrease in the incidence of hepatocellular carcinoma (HCC); however, it is unclear whether DAAs prevent the recurrence of HCC after curative treatment for HCC. This study aimed to prospectively investigate HCC recurrence and its predictors after curative treatment for HCC. Methods A total of 3012 patients with chronic HCV infection, with or without cirrhosis, who were treated with DAAs were enrolled between January 1, 2015 and January 31, 2017 as per the institutional review board approved study protocol at 15 institutions, including 10 university hospitals and five high‐volume centers in the Kyusyu area of Japan. Of the 3012 patients, 459 patients who had HCC but were cured with surgery or ablation therapy (curative treatment) before the use of DAAs were included in the analysis. Results During a mean follow‐up period of 29.4 months, 217 (47.2%) patients developed HCC recurrence. The median time to recurrence was 34.0 months, and the 1‐, 2‐, and 3‐year cumulative HCC recurrence rates were 27.1%, 43.4%, and 50.8%, respectively. The risk factors for HCC recurrence were the α‐fetoprotein (AFP) level before DAA therapy (P = 0.0047) and the number of curative treatments for HCC before DAA therapy (P

Published
2019
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15. Serum kynurenine levels are a novel biomarker to predict the prognosis of patients with hepatocellular carcinoma.

Author

Shigemune Bekki, Satoru Hashimoto, Kazumi Yamasaki, Atsumasa Komori, Seigo Abiru, Shinya Nagaoka, Akira Saeki, Tomoyuki Suehiro, Yuki Kugiyama, Asami Beppu, Tamotsu Kuroki, Minoru Nakamura, Masahiro Ito, and Hiroshi Yatsuhashi

Subjects
Medicine, Science
Abstract

BackgroundWe examined serum kynurenine levels in patients with chronic hepatitis C virus infection, and the relationship between serum kynurenine and prognosis in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C.MethodsWe retrospectively analyzed 604 patients with HCC diagnosed between January 1999 and December 2015, and 288 patients without HCC who were seen at the National Hospital Organization Nagasaki Medical Center between October 2014 and November 2017. The association between serum kynurenine and prognosis was evaluated using the Cox's proportional hazards regression analysis.ResultsPatients with HCC had significantly higher values of serum kynurenine than patients without HCC (median: 557.1 vs. 464.2 ng/mL, pConclusionsA high level of serum kynurenine correlated with poor prognosis of HCC. Serum kynurenine levels may be a novel biomarker to predict the prognosis of patients with HCC. The development of drugs that inhibit kynurenine production is expected to help improve the prognosis of patients with HCC.

Published
2020
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16. Association of soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) and mac-2 binding protein glycosylation isomer (M2BPGi) in patients with autoimmune hepatitis.

Author

Kiyoshi Migita, Minoru Nakamura, Yoshihiro Aiba, Hideko Kozuru, Seigo Abiru, Atsumasa Komori, Yuya Fujita, Junpei Temmoku, Tomoyuki Asano, Shuzo Sato, Makiko Furuya, Atsushi Naganuma, Kaname Yoshizawa, Masaaki Shimada, Keisuke Ario, Tomohiko Mannami, Hiroshi Kohno, Toshihiko Kaneyoshi, Takuya Komura, Hiromasa Ohira, and Hiroshi Yatsuhashi

Subjects
Medicine, Science
Abstract

BackgroundAutoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver injury progress to cirrhosis or hepatocellular carcinoma (HCC). The aim of the present study was to determine whether circulating soluble TIM3 (sTIM3) is elevated in patients with AIH patients and whether sTIM-3 levels are associated with clinical parameters of AIH.MethodsWe enrolled 123 Japanese patients with AIH who were identified from the National Hospital Organization-AIH-liver-network database, as well as 32 patients with chronic hepatitis C (CHC), 30 patients with primary biliary cholangitis (PBC) and healthy control subjects. Serum sTIM-3 concentrations were quantified by ELISA.ResultsSerum levels of sTIM-3 were significantly higher in AIH patients (median 4865 pg/ml; [interquartile range (IQR); 3122-7471]) compared to those in CHC (1026 pg/ml [IQR: 806-1283] pConclusionsCirculating sTIM-3 levels were elevated in AIH patients and are associated with AIH disease activity and AIH-related liver damage. These findings indicate that serum sTIM-3 correlated with disease status of AIH and could be useful biomarkers to detect autoimmune-mediated liver injury. Our data suggest a possible link between the TIM-3/GAL-9 pathway and AIH severity or phenotype, and further investigations of the TIM-3 pathway and AIH pathophysiology is warranted.

Published
2020
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17. Tofacitinib inhibits granulocyte–macrophage colony-stimulating factor-induced NLRP3 inflammasome activation in human neutrophils

Author

Makiko Yashiro Furuya, Tomoyuki Asano, Yuya Sumichika, Shuzo Sato, Hiroko Kobayashi, Hiroshi Watanabe, Eiji Suzuki, Hideko Kozuru, Hiroshi Yatsuhashi, Tomohiro Koga, Hiromasa Ohira, Hideharu Sekine, Atsushi Kawakami, and Kiyoshi Migita

Subjects
Granulocyte–macrophage colony-stimulating factor, Inflammasome, Interleukin-1 beta, Janus kinase, Neutrophils, NLR family pyrin domain-containing 3, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background Granulocyte–macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine that activates myeloid cells to initiate tissue inflammation. However, the molecular actions of GM-CSF against innate immunity are still poorly characterized. Here, we investigated the in vitro effects of GM-CSF on the activation of human myeloid lineages, neutrophils, and the underlying intracellular signaling mechanism, including inflammasome activation. Methods Human neutrophils were stimulated with GM-CSF in the presence or absence of tofacitinib. The cellular supernatants were analyzed for interleukin-1 beta (IL-1β) and caspase-1 by enzyme-linked immunosorbent assay (ELISA) methods. Pro-IL-1β mRNA expressions in human neutrophils were analyzed by real-time polymerase chain reaction. Protein phosphorylation of neutrophils was assessed by Western blot using phospho-specific antibodies. Results Stimulation with GM-CSF alone, but not tumor necrosis factor-alpha, was shown to increase the release of IL-1β and cleaved caspase-1 (p20) from human neutrophils. Tofacitinib, which inhibits GM-CSF–induced Janus kinase 2 (Jak2)-mediated signal transduction, completely abrogated GM-CSF–induced IL-1β and caspase-1 (p20) secretion from neutrophils. GM-CSF stimulation also induced pro-IL-1β mRNA expression in neutrophils and induced NLR family pyrin domain-containing 3 (NLRP3) protein expression. Although tofacitinib pretreatment marginally inhibited GM-CSF–induced pro-IL-1β mRNA expression, tofacitinib completely abrogated NLRP3 protein expression in neutrophils. Conclusions These results indicate that GM-CSF signaling induces NLRP3 expression and subsequent IL-1β production by affecting neutrophils, which may cause the activation of innate immunity. Therefore, GM-CSF is a key regulator of the NLRP3 inflammasome and IL-1β production by activating innate immune cells. This process can be blocked by tofacitinib, which interferes with JAK/STAT signaling pathways.

Published
2018
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18. HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype.

Author

Shomi Oka, Hiroshi Furukawa, Michio Yasunami, Aya Kawasaki, Hitomi Nakamura, Minoru Nakamura, Atsumasa Komori, Seigo Abiru, Shinya Nagaoka, Satoru Hashimoto, Atsushi Naganuma, Noriaki Naeshiro, Kaname Yoshizawa, Haruhiro Yamashita, Keisuke Ario, Hajime Ohta, Hironori Sakai, Iwao Yabuuchi, Atsushi Takahashi, Kazumichi Abe, Hiroshi Yatsuhashi, Shigeto Tohma, Hiromasa Ohira, Naoyuki Tsuchiya, and Kiyoshi Migita

Subjects
Medicine, Science
Abstract

Autoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH.HLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed.The predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62-5.43), DRB1*04:05 (P = 1.89×10-21, Pc = 5.86×10-20, OR 3.41, 95% CI 2.65-4.38), and DQB1*04:01 (P = 4.66×10-18, Pc = 6.99×10-17, OR 3.89, 95% CI 2.84-5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32-0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10-9, OR 3.52, 95% CI 2.34-5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45-424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10-6, OR 10.64, 95% CI 3.19-35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without.The important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.

Published
2017
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19. Rapid Increase in Serum Low-Density Lipoprotein Cholesterol Concentration during Hepatitis C Interferon-Free Treatment.

Author

Satoru Hashimoto, Hiroshi Yatsuhashi, Seigo Abiru, Kazumi Yamasaki, Atsumasa Komori, Shinya Nagaoka, Akira Saeki, Shinjiro Uchida, Shigemune Bekki, Yuki Kugiyama, Kazuyoshi Nagata, Minoru Nakamura, Kiyoshi Migita, and Kazuhiko Nakao

Subjects
Medicine, Science
Abstract

BACKGROUND & AIM:We performed lipid analyses at the early period of therapy in patients with chronic hepatitis C who underwent interferon (IFN)-free direct-acting antiviral (DAA) treatment, and we attempted to identify the factors that contributed to a rapid increase in the patients' serum low-density lipoprotein cholesterol (LDL-C) concentration. METHODS:We retrospectively analyzed the cases of 100 consecutive patients with HCV infection treated at the National Hospital Organization Nagasaki Medical Center: 24 patients underwent daclatasvir (DCV) and asunaprevir (ASV) combination therapy (DCV/ASV) for 24 weeks, and the other 76 patients underwent ledipasvir and sofosbuvir combination therapy (LDV/SOF) for 12 weeks. ΔLDL-C was defined as the changed in LDL-C level at 28 days from the start of therapy. To determine whether ΔLDL-C was associated with several kinds of factors including viral kinetics, we performed a stepwise multiple linear regression analysis. RESULTS:The LDL-C levels in patients treated with LDV/SOF were markedly and significantly elevated (87.45 to 122.5 mg/dl; p

Published
2016
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20. Association between Anti-Ganglionic Nicotinic Acetylcholine Receptor (gAChR) Antibodies and HLA-DRB1 Alleles in the Japanese Population.

Author

Yasuhiro Maeda, Kiyoshi Migita, Osamu Higuchi, Akihiro Mukaino, Hiroshi Furukawa, Atsumasa Komori, Minoru Nakamura, Satoru Hashimoto, Shinya Nagaoka, Seigo Abiru, Hiroshi Yatsuhashi, Hidenori Matsuo, Atsushi Kawakami, Michio Yasunami, and Shunya Nakane

Subjects
Medicine, Science
Abstract

Anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies are observed in autoimmune diseases, as well as in patients with autoimmune autonomic ganglionopathy. However, the genetic background of anti-gAChR antibodies is unclear. Here, we investigated HLA alleles in autoimmune hepatitis (AIH) patients with or without anti-gAChR antibodies.Genomic DNA from 260 patients with type-1 autoimmune hepatitis (AIH) were genotyped for HLA-A, B, DRB1, and DQB1 loci. Anti-gAChR antibodies in the sera form AIH patients were measured using the luciferase immunoprecipitation system, and examined allelic association in patients with or without anti-gAChR antibodies.We detected anti-α3 or -β4 gAChR antibodies in 11.5% (30/260) of patients with AIH. Among AIH patients there was no significant association between HLA-A, B DQB1 alleles and the positivity for anti-gAChR antibodies. Whereas the HLA-DRB1*0403 allele showed a significantly increased frequency in AIH patients with anti-gAChR antibodies compared with those without anti-gAChR antibodies.The frequency of the HLA-DRB1*0403 allele differed among Japanese patients with AIH according to the presence or absence of anti-gAChR antibodies. Our findings suggest that particular HLA class II molecules might control the development of anti-gAChR antibodies in the autoimmune response to gAChR.

Published
2016
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21. Histological Remission during Corticosteroid Therapy of Overlapping Nonalcoholic Steatohepatitis and Autoimmune Hepatitis: Case Report and Literature Review

Author

Shinichiroh Fukuda, Atsumasa Komori, Masahiro Itoh, Yumi Mihara, Satoru Hashimoto, Sung Kwan Bae, Shinya Nagaoka, Seigo Abiru, Hiroshi Yatsuhashi, and Hiromi Ishibashi

Subjects
Histological remission, Nonalcoholic steatohepatitis, Autoimmune hepatitis, Corticosteroid therapy, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Concurrence of nonalcoholic steatohepatitis (NASH) with autoimmune hepatitis (AIH) is a rare condition that is challenging to diagnosis, due to the relatively high prevalence of autoantibodies in NASH. It is also difficult to determine the most effective treatment as corticosteroids are likely to worsen NASH despite being effective in the treatment of AIH. In this case report, we present a female diagnosed with NASH-AIH overlap with accompanying diabetes mellitus, who successfully achieved normalization of serum alanine aminotransferase levels following prednisolone therapy and weight loss. A follow-up liver biopsy performed 40 months after the initial diagnosis showed only minimal inflammatory infiltrates in the portal area without any NASH histology. Resolution of NASH, in conjunction with a reduction in hepatic fibrosis, might suggest that prednisolone itself does not aggravate steatohepatitis, but rather prevents disease progression. Appropriate immunosuppressive treatment may therefore be an important component of the optimum therapy for NASH-AIH overlap.

Published
2011
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22. Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Values Predict the Development of Hepatocellular Carcinoma among Patients with Chronic Hepatitis C after Sustained Virological Response.

Author

Ryu Sasaki, Kazumi Yamasaki, Seigo Abiru, Atsumasa Komori, Shinya Nagaoka, Akira Saeki, Satoru Hashimoto, Shigemune Bekki, Yuki Kugiyama, Atsushi Kuno, Masaaki Korenaga, Akira Togayachi, Makoto Ocho, Masashi Mizokami, Hisashi Narimatsu, Tatsuki Ichikawa, Kazuhiko Nakao, and Hiroshi Yatsuhashi

Subjects
Medicine, Science
Abstract

Measurement of Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+-M2BP) in serum was recently shown to be a noninvasive method to assess liver fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP values to predict the development of hepatocellular carcinoma (HCC) in patients who achieved a sustained virological response (SVR) by interferon treatment. For this purpose, we retrospectively analyzed 238 patients with SVR who were treated with interferon in our department. Serum WFA+-M2BP values were measured at pre-treatment (pre-Tx), post-treatment (24 weeks after completion of interferon; post-Tx), the time of HCC diagnosis, and the last clinical visit. Of 238 patients with SVR, HCC developed in 16 (6.8%) patients. The average follow-up period was 9.1 years. The cumulative incidence of HCC was 3.4% at 5 years and 7.5% at 10 years. The median pre-Tx and post-Tx WFA+-M2BP values were 1.69 (range: 0.28 to 12.04 cutoff index (COI)) and 0.80 (range: 0.17 to 5.29 COI), respectively. The WFA+-M2BP values decreased significantly after SVR (P < 0.001). The median post-Tx WFA+-M2BP value in patients who developed HCC was significantly higher than that in patients who did not (P < 0.01). Multivariate analysis disclosed that age (> 60 years), sex (male), pre-Tx platelet count (< 15.0×10(3)/μL), and post-Tx WFA+-M2BP (> 2.0 COI) were associated with the development of HCC after SVR. Conclusion: Post-Tx WFA+-M2BP (> 2.0 COI) is associated with the risk for development of HCC among patients with SVR. The WFA+-M2BP values could be a new predictor for HCC after SVR.

Published
2015
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23. Circulating microRNA Profiles in Patients with Type-1 Autoimmune Hepatitis.

Author

Kiyoshi Migita, Atsumasa Komori, Hideko Kozuru, Yuka Jiuchi, Minoru Nakamura, Michio Yasunami, Hiroshi Furukawa, Seigo Abiru, Kazumi Yamasaki, Shinya Nagaoka, Satoru Hashimoto, Shigemune Bekki, Hiroshi Kamitsukasa, Yoko Nakamura, Hajime Ohta, Masaaki Shimada, Hironao Takahashi, Eiji Mita, Taizo Hijioka, Haruhiro Yamashita, Hiroshi Kouno, Makoto Nakamuta, Keisuke Ario, Toyokichi Muro, Hironori Sakai, Kazuhiro Sugi, Hideo Nishimura, Kaname Yoshizawa, Takeaki Sato, Atsushi Naganuma, Tatsuji Komatsu, Yukio Oohara, Fujio Makita, Minoru Tomizawa, and Hiroshi Yatsuhashi

Subjects
Medicine, Science
Abstract

Recent studies have demonstrated that micro (mi)RNA molecules can be detected in the circulation and can serve as potential biomarkers of various diseases. This study used microarray analysis to identify aberrantly expressed circulating miRNAs in patients with type 1 autoimmune hepatitis (AIH) compared with healthy controls. Patients with well-documented and untreated AIH were selected from the National Hospital Organization (NHO)-AIH-liver-network database. They underwent blood sampling and liver biopsy with inflammation grading and fibrosis staging before receiving treatment. To further confirm the microarray data, circulating expression levels of miR-21 and miR-122 were quantified by real-time quantitative polymerase chain reaction in 46 AIH patients, 40 patients with chronic hepatitis C (CHC), and 13 healthy controls. Consistent with the microarray data, serum levels of miR-21 were significantly elevated in AIH patients compared with CHC patients and healthy controls. miR-21 and miR-122 serum levels correlated with alanine aminotransferase levels. Circulating levels of miR-21 and miR-122 were significantly reduced in AIH patients with liver cirrhosis, and were inversely correlated with increased stages of fibrosis. By contrast, levels of circulating miR-21 showed a significant correlation with the histological grades of inflammation in AIH. We postulate that aberrantly expressed serum miRNAs are potential biomarkers of AIH and could be implicated in AIH pathogenesis. Alternations of miR-21 and miR-122 serum levels could reflect their putative roles in the mediation of inflammatory processes in AIH.

Published
2015
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24. Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population.

Author

Kiyoshi Migita, Minoru Nakamura, Seigo Abiru, Yuka Jiuchi, Shinya Nagaoka, Atsumasa Komori, Satoru Hashimoto, Shigemune Bekki, Kazumi Yamasaki, Tatsuji Komatsu, Masaaki Shimada, Hiroshi Kouno, Taizo Hijioka, Motoyuki Kohjima, Makoto Nakamuta, Michio Kato, Kaname Yoshizawa, Hajime Ohta, Yoko Nakamura, Eiichi Takezaki, Hideo Nishimura, Takeaki Sato, Keisuke Ario, Noboru Hirashima, Yukio Oohara, Atsushi Naganuma, Toyokichi Muro, Hironori Sakai, Eiji Mita, Kazuhiro Sugi, Haruhiro Yamashita, Fujio Makita, Hiroshi Yatsuhashi, Hiromi Ishibashi, and Michio Yasunami

Subjects
Medicine, Science
Abstract

Background/aimsRecent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study.Methodology/principal findingsGenomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23-2.11; P = 0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13-1.99; P = 0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44) or without liver cirrhosis (n = 186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies).Conclusions/significanceThis is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.

Published
2013
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25. Baseline Serum Cholesterol Is Associated with a Response to Pegylated Interferon Alfa-2b and Ribavirin Therapy for Chronic Hepatitis C Genotype 2

Author

Naota Taura, Tatsuki Ichikawa, Hisamitsu Miyaaki, Yoshiko Kadokawa, Takuya Tsutsumi, Shotaro Tsuruta, Yuji Kato, Osami Inoue, Noboru Kinoshita, Kazuo Ohba, Hiroyuki Kato, Kazuyuki Ohata, Junichi Masuda, Keisuke Hamasaki, Hiroshi Yatsuhashi, and Kazuhiko Nakao

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background. HCV infection is associated with lipid disorders because this virus utilizes the host lipid metabolism to sustain its life cycle. Several studies have indicated that higher concentrations of serum cholesterol and LDL before treatment are important predictors of higher rates of sustained virological response (SVR). However, most of these studies involved patients infected with HCV genotype 1. Thus, we performed a multi-institutional clinical study to evaluate the impact of lipid profiles on SVR rates in patients with HCV genotype 2. Methods. A total of 100 chronic hepatitis C patients with HCV genotype 2 who received peg-IFN alfa-2b and ribavirin therapy were consecutively enrolled. The significance of age, sex, BMI, AST level, ALT level, WBC, hemoglobin, platelet count, gamma-glutamyltransferase, total cholesterol level (TC), LDL level, HCV RNA, and histological evaluation was examined for SVR using logistic regression analysis. Results. The 100 patients infected with HCV genotype 2 were divided into 2 groups, an SVR group and a non-SVR group. Characteristics of each group were subsequently compared. There was no significant difference in the level of HCV RNA, BMI, platelet, TG, or stage of fibrosis between the groups. However, there were significant differences in the levels of TC and LDL-C. In multivariate logistic regression analysis using baseline characteristics, high TC level was an independent and significant risk factor (relative risk 18.59, P=0.015) for SVR. Conclusion. Baseline serum total cholesterol levels should be considered when assessing the likelihood of sustained treatment response following the course of peg-IFN and ribavirin therapy in patients with chronic HCV genotype 2 infection.

Published
2012
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26. Comparison of Efficacy and Safety of Atezolizumab Plus Bevacizumab and Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis

Author

Takashi Niizeki, Takayuki Tokunaga, Yuko Takami, Yoshiyuki Wada, Masaru Harada, Michihiko Shibata, Kazuhiko Nakao, Ryu Sasaki, Fumihito Hirai, Satoshi Shakado, Tomoharu Yoshizumi, Shinji Itoh, Hiroshi Yatsuhashi, Shigemune Bekki, Akio Ido, Seiichi Mawatari, Koichi Honda, Rie Sugimoto, Takeshi Senju, Hirokazu Takahashi, Takuya Kuwashiro, Tatsuji Maeshiro, Makoto Nakamuta, Yoshifusa Aratake, Tsutomu Yamashita, Yuichiro Otsuka, Shuichi Matsumoto, Tetsuro Sohda, Shigeo Shimose, Kenta Murotani, and Yasuhito Tanaka

Subjects
Bevacizumab, Cancer Research, Carcinoma, Hepatocellular, Oncology, Liver Neoplasms, Humans, Pharmacology (medical), Propensity Score, Retrospective Studies
Abstract

A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear.This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC.This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed.After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007).ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN.

Published
2022

27. Trends of hepatitis B virus genotype distribution in chronic hepatitis B patients in Japan

Author

Kazumasa, Sakamoto, Kiyoaki, Ito, Hiroshi, Yotsuyanagi, Hiroshi, Yatsuhashi, Yasuhito, Tanaka, Shuhei, Hige, Yasuhiro, Takikawa, Yoshiyuki, Ueno, Kazuhide, Yamamoto, Fumio, Imazeki, Jun, Inoue, Masayuki, Kurosaki, Takeji, Umemura, Hidenori, Toyoda, Eiji, Mita, Kojiro, Michitaka, Tatsuji, Maeshiro, Norie, Yamada, Atsushi, Suetsugu, Miwa, Kawanaka, Yuya, Seko, Kentaro, Matsuura, Akinori, Okumura, Yoshitaka, Fukuzawa, Masaya, Sugiyama, Masashi, Mizokami, and Masashi, Yoneda

Subjects
Young Adult, Hepatitis B virus, Hepatitis B, Chronic, Japan, Genotype, DNA, Viral, Gastroenterology, Humans, Hepatitis B, Aged
Abstract

Hepatitis B virus (HBV) is one of the most prevalent chronic viral infections that causes chronic hepatitis B (CHB). In Japan, genotypes B and C account for most of acute and chronic cases of hepatitis. However, previous studies showed that the prevalence of genotype A in CHB gradually increased every 5 years. Therefore, we have conducted a nationwide survey to comprehensively investigate the trends of HBV genotype distribution in CHB patients in Japan.4421 CHB patients were recruited between 2015 and 2016. Clinical characteristics and distribution of CHB patients among different age groups and genotypes in 2015-2016 was compared with those in 2000-2001, 2005-2006, and 2010-2011.The percentages of genotype A, B, C, and D were 4.0, 16.2, 79.1, and 0.7%, respectively. While the overall percentage of CHB patients with genotype A did not change in the past 5 years, CHB with genotype A increased in young adults. On the other hand, the peak distribution of CHB with genotypes B and C, two genotypes with the largest patient population, has shifted to an older age group.In Japan, the peak distribution for CHB with genotypes B and C advanced to an older age group while CHB with genotype A expanded in a younger age group. Given the universal HBV vaccination launch in Japan in 2016, these pre-vaccination survey data provide important baseline information for comparative studies of the impact of universal vaccination on HBV genotypes.

Published
2022

28. Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis

Author

Yuki Tahata, Hayato Hikita, Satoshi Mochida, Nobuyuki Enomoto, Norifumi Kawada, Masayuki Kurosaki, Akio Ido, Daiki Miki, Hitoshi Yoshiji, Yasuhiro Takikawa, Ryotaro Sakamori, Yoichi Hiasa, Kazuhiko Nakao, Naoya Kato, Yoshiyuki Ueno, Hiroshi Yatsuhashi, Yoshito Itoh, Ryosuke Tateishi, Goki Suda, Taro Takami, Yasunari Nakamoto, Yasuhiro Asahina, Kentaro Matsuura, Taro Yamashita, Tatsuya Kanto, Norio Akuta, Shuji Terai, Masahito Shimizu, Satoshi Sobue, Tomokatsu Miyaki, Akihiro Moriuchi, Ryoko Yamada, Takahiro Kodama, Tomohide Tatsumi, Tomomi Yamada, and Tetsuo Takehara

Subjects
Liver Cirrhosis, Male, Carcinoma, Hepatocellular, Sustained Virologic Response, Liver Neoplasms, Gastroenterology, Humans, Hepacivirus, Hepatitis C, Chronic, Antiviral Agents
Abstract

Direct-acting antiviral (DAA) therapy enables a high rate of sustained virologic response (SVR) in patients with hepatitis C virus associated cirrhosis. However, the impact of DAA therapy on liver-related events in patients with cirrhosis is unclear.A total of 350 patients with compensated and decompensated cirrhosis administered DAA therapy at 29 Japanese hospitals were enrolled (Child-Pugh class A [CP-A]: 195 patients, CP-B: 131 patients and CP-C: 24 patients).The SVR rates of patients with CP-A, CP-B and CP-C were 96.9%, 93.1% and 83.3%, respectively (p = 0.006). Seventy patients developed hepatocellular carcinoma (HCC), and male sex, previous HCC treatment, platelet counts 10.0 × 10HCC development and mortality in patients with CP-B were not different from those with CP-A. On the other hand, in patients with CP-C, the development of HCC and decompensated cirrhotic events requiring hospital admission, and death were frequent.University Hospital Medical Information Network (UMIN000036150).

Published
2022

29. Prognosis of patients with liver cirrhosis: A multi‐center retrospective observational study

Author

Atsushi Naganuma, Tatsuji Komatsu, Shinji Katsushima, Yutaka Mano, Kiyohide Fushimi, Hiroshi Kamitsukasa, Taisuke Jo, Tsutomu Yamashita, Hiromasa Horiguchi, Hayato Yamana, Hideo Yasunaga, Keisuke Ario, Hiroshi Yatsuhashi, Rie Sugimoto, Shinobu Imai, Satoru Tsuruta, and Kazumi Yamasaki

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Proportional hazards model, Retrospective cohort study, medicine.disease, Gastroenterology, Infectious Diseases, Esophageal varices, Internal medicine, Etiology, Medicine, Risk factor, business, Liver cancer, Cohort study
Abstract

Aim Despite advances in the management of liver diseases and changes in the etiology of cirrhosis, few studies have updated the prognosis of cirrhosis. This study aimed to clarify the recent prognosis of cirrhosis and identify risk factors for death. Methods In this retrospective observational study by the Hepatic Disease Network of the National Hospital Organization in Japan, chart reviews were performed to follow patients with cirrhosis beginning in 2011. We conducted Kaplan-Meier survival time analyses stratified by Child-Pugh classification and albumin-bilirubin grade. Cox regression analysis was used to identify risk factors for death. Results We identified 444 eligible patients from 25 hospitals, including 303 (68%), 110 (25%), and 31 (7%) patients with Child-Pugh classes A, B, and C, respectively. Hepatitis C virus infection was the cause of cirrhosis for 63% of the patients. The 1-year and 5-year cumulative survival rates of patients with Child-Pugh classes A, B, and C were 90% and 61%, 78% and 42%, and 65% and 25%, respectively. The 1-year and 5-year cumulative survival rates of patients with albumin-bilirubin grades 1, 2, and 3 were 98% and 80%, 91% and 56%, and 58% and 23%, respectively. Cirrhosis classification (Child-Pugh and albumin-bilirubin), age, liver cancer, and untreated esophageal varices were associated with increased hazard of death. Conclusions Little improvement was observed in the prognosis of cirrhosis compared with previous reports, and the prognosis of Child-Pugh class C cirrhosis remained poor. Untreated esophageal varices were identified as a risk factor for death.

Published
2021

30. Feasibility, safety and tolerability of the CREB-binding protein/β-catenin inhibitor OP-724 in patients with advanced primary biliary cholangitis: an investigator-initiated, open-label, non-randomised, two-centre, phase 1 study

Author

Masamichi Kimura, Eiichi Ogawa, Kenichi Harada, Jun Imamura, Masanao Saio, Yoshihiro Ikura, Hiroshi Yatsuhashi, Kazumoto Murata, Kouichi Miura, Ichiro Ieiri, Atsushi Tanaka, and Kiminori Kimura

Subjects
Liver Cirrhosis, Biliary, Gastroenterology, Humans, Feasibility Studies, CREB-Binding Protein, beta Catenin, Research Personnel, Aged
Abstract

ObjectiveThis study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/β-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC).DesignAn open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score.ResultsSeven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis.ConclusionAdministration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted.Trial registration numberNCT04047160.

Published
2022

31. Real‐world hospital mortality of liver cirrhosis inpatients in Japan: a large‐scale cohort study using a medical claims database

Author

Takahiro Hirano, Hiromi Sano, Hiroshi Yatsuhashi, and Yoshiyuki Shibasaki

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Tolvaptan, Retrospective cohort study, medicine.disease, Infectious Diseases, Internal medicine, Ascites, medicine, Etiology, Liver function, medicine.symptom, business, Survival rate, Cohort study, medicine.drug
Abstract

Aim Prognosis of liver cirrhosis patients is poor when ascites is present and liver function is impaired, but such up-to-date information from a large-scale, real-world setting is limited in Japan. We aimed to investigate the hospital mortality of Japanese liver cirrhosis inpatients. Methods This retrospective cohort study included data on liver cirrhosis inpatients between January 2011 and September 2018 extracted from an administrative claims database. The outcome was in-hospital mortality. The 1- and 3-year cumulative survival rates were examined for liver cirrhosis etiology, Child-Pugh classification, or ascites presence/absence using Kaplan-Meier analysis. The survival up to 1 year for tolvaptan prescription/nonprescription was examined. Results We analyzed the data of 57 769 inpatients. Survival rates did not substantially differ among etiologies, with a better prognosis for alcohol etiology and poorer prognosis for hepatitis C virus. According to the Child-Pugh classification, the 1- and 3-year survival rates were 90.2% and 75.3% for grade A, 73.5% and 53.9% for grade B, and 41.9% and 28.9% for grade C, respectively. Patients without ascites had a higher survival rate (83.2% and 67.0% at 1 and 3 years, respectively) than those with ascites (51.9% and 36.3%, respectively). Based on examining matched patients with ascites using a propensity score, prognosis was poor in general but was better at 6 months (58.1%) or similar at 1 year (47.1%) in patients prescribed tolvaptan compared to those not prescribed tolvaptan (54.8% and 47.5%, respectively). Conclusions Poorer prognosis was suggested in inpatients with cirrhosis who had a worse Child-Pugh grade and ascites.

Published
2021

32. Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines

Author

Osamu Yokosuka, Tatsuo Kanda, Seik-Soon Khor, Masaya Sugiyama, Hirohisa Yazaki, Nao Nishida, Aiko Sakai, Keisuke Kakisaka, Hiroshi Yatsuhashi, Katsushi Tokunaga, Yosuke Kawai, Jun Ohashi, Miyuki Ishikawa, Yasuhiro Takikawa, Yuichiro Eguchi, Akihiro Tamori, Masashi Mizokami, Keisuke Hino, Sohji Nishina, Kaori Okudera, Kazumi Yamasaki, Takayo Tsuchiura, Ryo Sumazaki, and Hiromi Sawai

Subjects
0301 basic medicine, Adult, Male, HBsAg, Hepatitis B virus, Science, Diseases, Human leukocyte antigen, Biology, Article, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Japan, HLA-DQ Antigens, Genetics, medicine, HLA-DQ beta-Chains, Humans, Hepatitis B Vaccines, Genetic association, Multidisciplinary, Hepatitis B Surface Antigens, Haplotype, Vaccination, Gastroenterology, Antibody titer, Hepatitis B, medicine.disease, 030104 developmental biology, Risk factors, Haplotypes, 030220 oncology & carcinogenesis, Immunology, Medicine, Female, Biomarkers, HLA-DRB1 Chains
Abstract

Hepatitis B (HB) vaccines (Heptavax-II and Bimmugen) designed based on HBV genotypes A and C are mainly used for vaccination against HB in Japan. To determine whether there are differences in the genetic background associated with vaccine responsiveness, genome-wide association studies were performed on 555 Heptavax-II and 1193 Bimmugen recipients. Further HLA imputation and detailed analysis of the association with HLA genes showed that two haplotypes, DRB1*13:02-DQB1*06:04 and DRB1*04:05-DQB1*04:01, were significantly associated in comparison with high-responders (HBsAb > 100 mIU/mL) for the two HB vaccines. In particular, HLA-DRB1*13:02-DQB1*06:04 haplotype is of great interest in the sense that it could only be detected by direct analysis of the high-responders in vaccination with Heptavax-II or Bimmugen. Compared with healthy controls, DRB1*13:02-DQB1*06:04 was significantly less frequent in high-responders when vaccinated with Heptavax-II, indicating that high antibody titers were less likely to be obtained with Heptavax-II. As Bimmugen and Heptavax-II tended to have high and low vaccine responses to DRB1*13:02, 15 residues were found in the Heptavax-II-derived antigenic peptide predicted to have the most unstable HLA-peptide binding. Further functional analysis of selected hepatitis B patients with HLA haplotypes identified in this study is expected to lead to an understanding of the mechanisms underlying liver disease.

Published
2021

33. Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study

Author

Takahiro Kodama, Tomomi Yamada, Norifumi Kawada, Ryosuke Tateishi, Masayuki Kurosaki, Nobuyuki Enomoto, Yasuhiro Asahina, Tatsuya Kanto, Goki Suda, Taro Yamashita, Tetsuo Takehara, Hitoshi Yoshiji, Daiki Miki, Yasuhiro Takikawa, Taro Takami, Yoshito Itoh, Kazuhiko Nakao, Shuji Terai, Tomohide Tatsumi, Ryotaro Sakamori, Akio Ido, Yoichi Hiasa, Hiroshi Yatsuhashi, Ryoko Yamada, Yasunari Nakamoto, Satoshi Mochida, Kentaro Matsuura, Naoya Kato, Yoshiyuki Ueno, Masahito Shimizu, Hayato Hikita, Norio Akuta, and Yuki Tahata

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Sustained Virologic Response, Sofosbuvir, Hepatitis C virus, Phases of clinical research, medicine.disease_cause, Antiviral Agents, Heterocyclic Compounds, 4 or More Rings, Gastroenterology, Drug Administration Schedule, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Japan, Internal medicine, medicine, Humans, Aged, Aged, 80 and over, business.industry, Hepatitis C, Chronic, Middle Aged, Hepatology, medicine.disease, Discontinuation, Drug Combinations, Treatment Outcome, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Carbamates, Liver function, business, Follow-Up Studies, medicine.drug
Abstract

Real-world data on the efficacy and safety of sofosbuvir plus velpatasvir (SOF/VEL) treatment for patients with hepatitis C virus (HCV)-related decompensated cirrhosis are limited in Japan. A total of 190 patients with compensated (108) or decompensated (82) cirrhosis who initiated direct-acting antiviral (DAA) treatment between February 2019 and August 2019 were enrolled. Sustained virologic response (SVR) was defined as undetectable serum HCV-RNA at 12 weeks after the end of treatment (EOT). The SVR12 rates were 92.6% in patients with compensated cirrhosis and 90.2% in patients with decompensated cirrhosis (p = 0.564), and the treatment completion rates were 98.1% and 96.3%, respectively (p = 0.372). In patients with decompensated cirrhosis, 3 patients discontinued treatment and 2 patients died because of liver-related events. In patients with decompensated cirrhosis with SVR12, 50% of patients with Child–Pugh class B at baseline showed improvement to class A at SVR12, and 27% and 9% of patients with Child–Pugh class C at baseline showed improvement to class B and class A at SVR12, respectively. Patients who achieved SVR12 showed elevated serum albumin levels at the EOT, which were further elevated at SVR12, but no elevated serum albumin levels after the EOT were observed in patients with baseline serum albumin levels less than 2.8 g/dl. Real-world efficacy of SOF/VEL treatment for patients with decompensated cirrhosis was similar to Japanese phase 3 study, although treatment discontinuation and death related to liver disease occurred. In patients with poor hepatic reserve, whether it improves continuously after viral clearance requires further evaluation.

Published
2020

35. <scp> Wisteria floribunda </scp> agglutinin‐positive human Mac‐2‐binding protein as a predictive marker of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients

Author

Kazumi Yamasaki, Koji Natsuda, Tomohiko Adachi, Susumu Eguchi, Masaaki Hidaka, Mitsuhisa Takatsuki, Shinichiro Ono, and Hiroshi Yatsuhashi

Subjects
Predictive marker, Hepatology, biology, business.industry, Hepatitis C virus, virus diseases, medicine.disease_cause, Wisteria floribunda, biology.organism_classification, medicine.disease, digestive system diseases, Type IV collagen, chemistry.chemical_compound, Infectious Diseases, chemistry, Fibrosis, Hyaluronic acid, Immunology, medicine, Coinfection, Liver function, business
Abstract

Aim In human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected patients, the progression of liver failure is reported to be more aggressive than that in HCV mono-infected patients. Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+ -M2BP) is well recognized as a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We analyzed HIV/HCV coinfected patients' M2BP levels as a possible marker for predicting liver fibrosis. Methods M2BP was measured in 31 HIV/HCV coinfected patients, and we analyzed the correlation between WFA+ -M2BP and several markers of fibrosis, liver function, and tumor markers. We compared the WFA+ -M2BP levels in HIV/HCV coinfected patients with those of HCV mono-infected patients by performing a propensity score matching analysis. Results In the HIV/HCV coinfected patients, the serum level of WFA+ -M2BP was well correlated with the markers type IV collagen, hyaluronic acid, and alpha-fetoprotein, but not protein induced by vitamin K absence-II. In the propensity score matching with HCV mono-infected patients, the WFA+ -M2BP levels were significantly higher in the HIV/HCV coinfected patients compared with the levels in the HCV mono-infected patients. Conclusion In conclusion, WFA+ -M2BP might be a feasible predictive marker of fibrosis in HIV/HCV coinfected patients.

Published
2020

36. Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Author

Toshiki Nikami, Hitomi Nakamura, Takuya Komura, Yuki Hitomi, Kiyoshi Migita, Atsushi Naganuma, Amane Kitasato, Olivier Gervais, Hiroshi Kouno, Atsumasa Komori, Hiromasa Ohira, Minae Kawashima, Hajime Ohta, Seigo Abiru, Yosuke Kawai, Shinji Katsushima, Kaname Yoshizawa, Kazuko Ueno, Hideo Nishimura, Masao Nagasaki, Tamotsu Kuroki, Tatsuji Komatsu, Katsushi Tokunaga, Hajime Takikawa, Shinya Nagaoka, Kazuhiko Yamauchi, Tomohiko Mannami, Seik-Soon Kohn, Kouki Matsushita, Tatsuro Kobata, Hirotaka Kouno, Nao Nishida, Satoru Tsuruta, Fujio Makita, Atsushi Tanaka, Hiroshi Yatsuhashi, Shinji Shimoda, Yoshihiro Aiba, Kazuhiro Sugi, Kaname Kojima, and Minoru Nakamura

Subjects
Messenger RNA, CD40, Hepatology, Microarray analysis techniques, Cell, Genome-wide association study, Original Articles, Computational biology, Biology, medicine.anatomical_structure, Gene expression, medicine, biology.protein, lcsh:Diseases of the digestive system. Gastroenterology, Original Article, lcsh:RC799-869, Gene, Genetic association
Abstract

Genome‐wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease‐susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single‐nucleotide polymorphisms (P 2 versus controls (P

Published
2020

37. JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study

Author

Yasuhiro Asahina, Toshikazu Nakano, Hiroshi Yatsuhashi, Yosuke Hagiwara, Tetsuo Takehara, Yuhan Huang, Hiroko Shimizu, Leen Vijgen, Yasuhito Tanaka, Masayuki Kurosaki, Naoki Hiramatsu, Akito Nozaki, Kazuaki Chayama, Norio Hayashi, Hiroki Yoshida, Naoya Sakamoto, and Michael Biermer

Subjects
Adult, Liver Cirrhosis, Male, Simeprevir, medicine.medical_specialty, Indoles, Cirrhosis, Genotype, Sustained Virologic Response, Hepatitis C virus, Hepacivirus, medicine.disease_cause, Antiviral Agents, Gastroenterology, Viral Relapse, Japan, Internal medicine, Clinical endpoint, Humans, Medicine, Adverse effect, Uridine, Aged, Original Article—Liver, Pancreas, and Biliary Tract, Alanine, business.industry, Hepatitis C, Chronic, Middle Aged, Hepatology, medicine.disease, Drug Combinations, Treatment Outcome, Cohort, Japanese, Phosphoramides, Odalasvir, Benzimidazoles, Female, Carbamates, AL-335, business, Follow-Up Studies
Abstract

Background The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis. Methods In this Phase IIa, open-label, multicenter study—OMEGA-3 (NCT02993250)—patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs). Results Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up. Conclusions In HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.

Published
2020

38. A case of liver abscess caused by Edwardsiella tarda with rapid increase and bacteremia

Author

Atsumasa Komori, Satoru Hashimoto, Akira Saeki, Asami Beppu, Kazumi Yamasaki, Hiroshi Yatsuhashi, Tomoyuki Suehiro, Shinya Nagaoka, Yuki Kugiyama, Shigemune Bekki, and Seigo Abiru

Subjects
Hepatology, biology, business.industry, Bacteremia, Edwardsiella tarda, medicine, biology.organism_classification, medicine.disease, business, Microbiology, Liver abscess
Published
2020

39. The impact of liver function improvement after direct-acting antiviral therapy on the outcome in hepatitis C virus patients with decompensated cirrhosis

Author

Yuki Tahata, Hayato Hikita, Satoshi Mochida, Nobuyuki Enomoto, Norifumi Kawada, Masayuki Kurosaki, Akio Ido, Hitoshi Yoshiji, Daiki Miki, Yasuhiro Takikawa, Ryotaro Sakamori, Yoichi Hiasa, Hiroshi Yatsuhashi, Kazuhiko Nakao, Naoya Kato, Yoshiyuki Ueno, Yoshito Itoh, Ryosuke Tateishi, Goki Suda, Taro Takami, Kentaro Matsuura, Taro Yamashita, Norio Akuta, Tatsuya Kanto, Yasunari Nakamoto, Yasuhiro Asahina, Shuji Terai, Masahito Shimizu, Ryoko Yamada, Takahiro Kodama, Tomohide Tatsumi, Tomomi Yamada, and Tetsuo Takehara

Subjects
Hepatology
Published
2022

40. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byun, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, Maria Consiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton V.J. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris D.J. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom J.W. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch'ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, and Charles Millson

Subjects
Science & Technology, Hepatology, Gastroenterology & Hepatology, Italian PBC Study Group, Japan-PBC-GWAS Consortium, UK-PBC Consortium, Chinese PBC Consortium, 1103 Clinical Sciences, US PBC Consortium, Canadian PBC Consortium, Life Sciences & Biomedicine, PBC Consortia, 1117 Public Health and Health Services
Published
2021

41. Treatment algorithm for thrombocytopenia in patients with chronic liver disease undergoing planned invasive procedures

Author

Hitoshi Yoshiji, Takuji Torimura, Masayuki Kurosaki, Yoshiyuki Ueno, Hiroshi Yatsuhashi, Koichiro Yamakado, and Etsuro Hatano

Subjects
Thrombopoietin Receptor Agonists, Blood transfusion, Hepatology, business.industry, medicine.medical_treatment, Chronic liver disease, medicine.disease, Clinical Practice, Infectious Diseases, Platelet transfusion, Expert opinion, medicine, In patient, business, Algorithm
Abstract

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgment and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice.

Published
2021

42. Trends in Hepatocellular Carcinoma Incidences in Japan Between 1996 and 2019

Author

Yoko Yoshimaru, Yoshifusa Aratake, Yuko Takami, Takuji Torimura, Makoto Nakamuta, Shotaro Sakisaka, Kenji Nagata, Tomoharu Yoshizumi, Seiichi Mawatari, Koichi Honda, Satoshi Shakado, Ryu Sasaki, Shinji Itoh, Hiroshi Yatsuhashi, Masaru Harada, Michihiko Shibata, Shigemune Bekki, Yasuji Komorizono, Tatsuji Maeshiro, Kazuhiko Nakao, Takashi Goto, Tetsuro Sohda, Satoshi Oeda, Yasuhito Tanaka, Tsutomu Yamashita, Akio Ido, Shuichi Matsumoto, and Masahito Nakano

Subjects
medicine.medical_specialty, business.industry, Hepatocellular carcinoma, Internal medicine, Medicine, business, medicine.disease, Gastroenterology, digestive system diseases
Abstract

Background: While the proportion of hepatocellular carcinoma (HCC) cases with non-viral etiology continues to increase in Japan, the epidemiological trends in the sex and age distribution of new HCC cases remain unclear. This study examines the epidemiological trends, including the distribution of sex, age, and disease etiology, in HCC incidence over 24 years.Methods: Data of 20,547 newly diagnosed HCC patients in 1996–2019 at 19 institutions participating in the Liver Cancer Study Group of Kyushu were analyzed in this prospective study. We divided the study period into four 6-year quarters. HCC etiology was categorized as hepatitis B virus (HBV) infection, HBV+hepatitis C virus (HCV) infection, HCV infection, and both negative (non-BC). Results: The incidences of HCC per quarter of the study period were 4,311 (21.0%), 5,505 (26.8%), 5,776 (28.1%), and 4,955 (24.1%) cases, sequentially. Overall, 14,020 (68.2%) patients were male. The number of HCC cases in patients ≤50 years, 60–69 years, 70–79 years, and ≥80 years were 3,711 (18.1%), 6,652 (32.4%), 7,448 (36.2%), and 2,736 (13.3%), respectively. The average age of newly diagnosed patients increased in each quarter. HCC was associated with HBV, HBV+HCV, and HCV infections and non-BC in 2,997 (14.6%), 187 (0.9%), and 12,019 (58.5%), and 5,344 (26.0%) cases, respectively. The number of HCV-associated cases decreased in each quarter, while that of non-BC-associated cases increased.Conclusions: HCC incidence tends to increase in the elderly and in non-BC patients; in contrast, HCC incidence due to HCV tends to decrease. In countries where HCV infection is likely the predominant cause of HCC, similar trends in HCC incidence are anticipated in the future.

Published
2021

43. Indications and waiting list priority for deceased donor liver transplantation in HIV/HCV co‐infected hemophilic patients in Japan through contaminated blood product

Author

Kunihisa Tsukada, Tetsuya Hara, Kiyoshi Hasegawa, Masahiro Shinoda, Hiroshi Yotsuyanagi, Hidetoshi Eguchi, Tsuyoshi Shimamura, Tomoko Uehira, Mitsuhisa Takatsuki, Hiroshi Yatsuhashi, Hiroto Egawa, Kazuhiko Nakao, Susumu Eguchi, Tomoyuki Endo, Masaaki Hidaka, Takuya Genda, Akihiko Soyama, Koji Natsuda, and Takanobu Hara

Subjects
Deceased donor, Pediatrics, medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, medicine.medical_treatment, Liver transplantation, medicine.disease, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Infectious Diseases, Acquired immunodeficiency syndrome (AIDS), Blood product, Waiting list, 030220 oncology & carcinogenesis, medicine, Portal hypertension, 030211 gastroenterology & hepatology, business
Abstract

HIV/HCV co-infection from blood products for hemophilia has been a social problem in Japan. Liver transplantation (LT) is an important treatment option for hepatic failure and cirrhosis of the liver in co-infected patients, and appropriate indications for LT, especially organ form deceased donors, are required by society. The aim is to propose priority status for the waiting list for deceased donor (DD) LT in HIV/HCV co-infected patients in Japan based on medical and scientific considerations. Since 2009, we have been working on the subject in research projects under grants-in-aid for health and labour sciences research on AIDS measures provided by the Ministry of Health, Labour and Welfare (the Kanematsu project and Eguchi project). Our research showed that hepatic fibrosis is advanced in HIV/HCV co-infected Japanese patients, especially those with hemophilia who became infected from blood products at a faster rate than HCV mono-infected patients. In addition, those patients who developed portal hypertension had a poor prognosis at a young age. The results of our research contributed to increasing the priority score of those patients on the deceased donor liver transplantation (DDLT) waiting list in 2013 and to establishing a scoring system for DDLT corresponding to the Model for End-stage Liver disease (MELD) score in 2019. This paper introduces changes in priority and the current state of priority of the DDLT waiting list for HIV/HCV co-infected patients in Japan.

Published
2021

44. Validity of administrative database detection of previously resolved hepatitis B virus in Japan

Author

Kiyoshi Migita, Hayato Yamana, Kiyohide Fushimi, Norihiko Inoue, Masaya Sugiyama, Shinobu Imai, Hiromasa Horiguchi, Masashi Mizokami, Hiroshi Yatsuhashi, and Manabu Akazawa

Subjects
Male, medicine.medical_specialty, disease control, reactivation, Hepatitis B virus, Databases, Factual, medicine.medical_treatment, Biostatistics, medicine.disease_cause, chemotherapy, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Japan, Administrative database, Predictive Value of Tests, Virology, Internal medicine, medicine, Humans, 030212 general & internal medicine, Research Articles, Aged, Retrospective Studies, Hepatitis, Immunosuppression Therapy, Chemotherapy, business.industry, Incidence (epidemiology), Incidence, Reproducibility of Results, Retrospective cohort study, Middle Aged, medicine.disease, Hepatitis B, Confidence interval, infection, Infectious Diseases, Rheumatoid arthritis, 030211 gastroenterology & hepatology, Female, Virus Activation, business, biostatistics and bioinformatics, Algorithms, Immunosuppressive Agents, Research Article
Abstract

The risk of hepatitis B virus (HBV) reactivation has increased owing to advances in the immunosuppressive therapy field. However, the HBV reactivation incidence among patients with previously resolved HBV (prHBV) infection during immunosuppressive therapy for rheumatoid arthritis (RA) remains unclear. The objective of this work is to describe the validity of detecting prHBV infection from administrative data through comparisons with chart abstraction and determine the incidence of HBV reactivation during immunosuppressive therapy for RA in Japan. In this retrospective cohort study, data on selected patients were extracted from administrative claims data. To identify patients with prHBV infection and de novo hepatitis, and HBsAg carriers, we conducted chart abstraction. The incidence rate of de novo hepatitis was 1.23 of 100 person‐years. The positive predictive value (PPV) and its 95% confidence interval (CI) of administrative data for the identification of suspected prHBV infections was 85.8% (95% CI: 81.7%‐89.3%). This study evaluated the PPV of the algorithm of HBV‐DNA testing with immunosuppressive therapy performed four times or more per year for the detection of prHBV infection from administrative data. Additionally, we determined the incidence rate of HBV reactivation among preHBV infections during immunosuppressive therapy for RA to be 1.23 of 100 person‐years.

Published
2019

45. Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study

Author

Yoko Yoshimaru, Hironori Koga, Takuji Torimura, Yuichiro Eguchi, Tatsuya Ide, Satoshi Shakado, Masataka Seike, Yutaka Sasaki, Satoshi Miuma, Satoru Hashimoto, Yuichi Honma, Shotaro Sakisaka, Satoshi Oeda, Yuko Takami, Seiichi Mawatari, Shuichi Matsumoto, Tatsuyuki Kakuma, Tatsuji Maeshiro, Makoto Nakamuta, Masahito Nakano, Kenji Nagata, Akio Ido, Hiroshi Yatsuhashi, Tetsuo Sohda, Masaru Harada, Kazuhiko Nakao, and Nobito Higuchi

Subjects
Adult, Male, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Sustained Virologic Response, Hepatitis C virus, medicine.disease_cause, Antiviral Agents, Gastroenterology, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Japan, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Aged, 80 and over, Hepatology, business.industry, Incidence, Incidence (epidemiology), Liver Neoplasms, Hepatitis C, Chronic, Middle Aged, medicine.disease, digestive system diseases, Colorectal surgery, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cohort, Female, 030211 gastroenterology & hepatology, Interferons, business
Abstract

While achieving sustained virological response (SVR) following interferon-based or direct-acting antiviral agent (DAA) treatments reduces the incidence of hepatocellular carcinoma (HCC), an increase in unexpected early occurrence or recurrence of HCC after hepatitis C virus elimination by DAA treatments has been reported. We prospectively investigated the incidence and risk factors of HCC after DAA treatment in a large multicenter cohort in Japan. Patients with chronic hepatitis C with or without cirrhosis who were treated with DAAs and obtained SVR were enrolled. DAAs were administered for 3 or 6 months. A total of 2552 patients were enrolled. Of these, 70 patients (2.7%) developed HCC. The 12-, 24-, and 36-month cumulative HCC incidences were 1.3%, 2.9%, and 4.9% in all patients; 2.5%, 5.2%, and 10.0% in those with cirrhosis; and 0.9%, 2.1%, and 2.9% in those without cirrhosis, respectively. Multivariate analysis revealed age, sex, gamma-glutamyl transpeptidase level, and fibrosis-4 index to be independent factors associated with HCC. Patients with these four factors had an approximately six-to-sevenfold increased risk for HCC development. Five patients with large and early tumor occurrence did not receive contrast imaging examinations before treatment. Although the results of our prospective study suggested that achieving SVR by DAA treatment reduces the incidence of HCC, HCC development still occurs. Careful follow-up is important in patients with risk factors.

Published
2019

46. Liver Function in Older Patients With Unresectable Hepatocellular Carcinoma After Administration of Lenvatinib

Author

Satoshi Matsuo, Satsuki Hashimoto, Ryu Sasaki, Toshihisa Matsuzaki, Yasuhide Motoyoshi, Noboru Kinoshita, Kazuo Ohba, Satoshi Miuma, Hidetaka Shibata, Hiroshi Yatsuhashi, Kazuhiko Nakao, Susumu Eguchi, Hisamitsu Miyaaki, Yuji Kato, Yuki Kugiyama, Masafumi Haraguchi, Masaaki Hidaka, Masanori Fukushima, Masaya Shigeno, and Shinichi Iwatsu

Subjects
Male, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, Gastroenterology, chemistry.chemical_compound, Older patients, Liver Function Tests, Internal medicine, Medicine, Humans, In patient, Age of Onset, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Phenylurea Compounds, Liver Neoplasms, Age Factors, General Medicine, Odds ratio, medicine.disease, Confidence interval, Oncology, chemistry, Liver, Hepatocellular carcinoma, Quinolines, Observational study, Female, Liver function, business, Lenvatinib
Abstract

Background The age of patients with advanced hepatocellular carcinoma (HCC) eligible for molecular-targeted drug treatment is increasing. We assessed liver function after lenvatinib administration according to age in patients with advanced HCC. Patients and methods In this retrospective, multicenter, observational study, we reviewed the records of patients with HCC who received lenvatinib treatment (March 2018-March 2020). Liver function was measured using the Albumin-Bilirubin Index (ALBI). Results Of 119 patients, with a median age of 72.0 years, median overall survival was 15.3 months. Overall survival was significantly better in the group which maintained liver function (p=0.02). Older age (≥72 years) was associated with liver-function deterioration within 8 weeks (odds ratio=2.47, 95% confidence interval=1.06-5.75, p=0.035). The ALBI score was significantly higher in the older group at 4 and 8 weeks after lenvatinib administration. Conclusion Lenvatinib administration was more likely to adversely affect liver function in older patients; dose adjustment should be considered in such patients.

Published
2021

47. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Ch'Ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byan J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Medical Research Council (MRC), LiveR North, Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .

Subjects
Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Published
2021

48. Albumin Platelet Product: A Novel Score for Liver Fibrosis Stage and Prognosis

Author

Koji Fujita, Kazumi Yamasaki, Asahiro Morishita, Tingting Shi, Joji Tani, Noriko Nishiyama, Hideki Kobara, Takashi Himoto, Hiroshi Yatsuhashi, and Tsutomu Masaki

Abstract

Fibrosis-4 index, a conventional biomarker for liver fibrosis stage, is confounded by age and hepatitis activity grade . The current retrospective multicenter study aimed to formulate the novel indices of liver fibrosis by mathematically combining items of peripheral blood examination and to evaluate ability of prognosis prediction. After a novel index was established in a training cohort, the index was tested in a validation cohort. Briefly, a total of 426 patients were enrolled in a training cohort. Albumin and platelet most strongly correlated to fibrosis stage among blood examination. Albumin platelet product (APP) = Albumin × platelet / 1000 could differentiate the four stages of liver fibrosis (p < 0.05). APP indicated fibrosis stage independent from hepatitis activity grade. A cut-off value = 4.349 diagnosed cirrhosis with area under ROC more than 0.8. Multivariate analysis revealed that smaller APP independently contributed to HCC prevalence and overall mortality. The results were validated in another 707 patients with HCV infection. In conclusion, APP was not confounded by age or hepatitis activity grade contrary to Fibrosis-4 index. APP is as simple as physicians can calculate it by pen calculation. The product serves physicians in managing patients with chronic liver disease.

Published
2020

49. Characteristics and Healthcare Costs in the Aging Hepatitis B Population of Japan: A Nationwide Real-World Analysis

Author

Craig Brooks-Rooney, Hiroshi Yatsuhashi, Masayuki Kurosaki, Alvin Ng, Mindie H. Nguyen, I-Heng Lee, and Hiroshi Yotsuyanagi

Subjects
Adult, medicine.medical_specialty, Aging, Cirrhosis, Osteoporosis, Population, Comorbidity, Japan, Internal medicine, Health care, medicine, Humans, education, Aged, Retrospective Studies, education.field_of_study, business.industry, Liver Neoplasms, Gastroenterology, General Medicine, Health Care Costs, Hepatitis B, Middle Aged, medicine.disease, Cross-Sectional Studies, Hepatocellular carcinoma, Charlson comorbidity index, business
Abstract

Introduction: Advancing age, comorbidity, and financial burden have been observed in chronic hepatitis B (CHB) patients globally. As Japan is leading the world in aging demographics, similar real-world data are urgently needed for its CHB population to inform all stakeholders. Methods: This cross-sectional study characterized the demographics, comorbidities, and healthcare costs of a large Japanese real-world adult (≥18 years) CHB patient (ICD-10: B18.1) population from the Medical Data Vision database from January 01, 2012, to December 31, 2016. Comorbidities were identified by ICD-10 codes, and the annual point prevalence and Charlson Comorbidity Index (CCI) score were calculated. Annual mean and median all-cause healthcare utilization and costs per patient were calculated. Comparison tests were conducted for CCI scores, prevalence of comorbidities, and healthcare resource utilization and costs. Results: We identified 11,125 CHB patients. Between 2012 and 2016, the mean age increased from 62.0 to 65.2 years, and the percentage of those aged ≥65 years increased from 45.6% to 60.7%. The prevalence of cirrhosis remained similar (5.8% in 2012 and 5.6% in 2016, p = 0.69) while hepatocellular carcinoma decreased from 6.3% to 4.5% (p < 0.01). The prevalence of nonliver comorbidities increased (40.9–52.0% for cancer [p < 0.01], 12.1–17.7% for osteoporosis [p < 0.01], and 10.7–15.0% for renal impairment [p < 0.01]). Healthcare resource utilization and costs also increased, with a 119.3% increase in median total healthcare costs from JPY 229,143 in 2012 to 502,467 in 2016 (p < 0.01). Conclusions: The CHB population of Japan is predominantly elderly and carry a high nonliver comorbidity burden, while incurring increasing healthcare costs.

Published
2020

50. JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells

Author

Kiyoshi Migita, Atsushi Kawakami, Hiroshi Yatsuhashi, Shuzo Sato, Tomoyuki Asano, Yuya Fujita, Haruki Matsumoto, Jumpei Temmoku, Hideko Kozuru, Hiroshi Watanabe, Naoki Matsuoka, and Makiko Furuya-Yashiro

Subjects
lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Neutrophils, THP-1 Cells, medicine.medical_treatment, Immunology, Pharmacology, Cell Line, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Piperidines, Baricitinib, STAT5 Transcription Factor, medicine, Humans, Janus Kinase Inhibitors, Rheumatoid arthritis, Receptor, STAT5, 030203 arthritis & rheumatology, Sulfonamides, Innate immune system, Tofacitinib, biology, Chemistry, Granulocyte-Macrophage Colony-Stimulating Factor, GM-CSF, Janus Kinase 2, Immunity, Innate, Pyrimidines, 030104 developmental biology, Cytokine, Purines, IL-1β, Antirheumatic Agents, Upadacitinib, Janus kinases, biology.protein, Azetidines, Pyrazoles, Phosphorylation, Signal transduction, lcsh:RC581-607, Janus kinase, Heterocyclic Compounds, 3-Ring, Signal Transduction, Research Article
Abstract

Background Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines. Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA. However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors. We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells. Results Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400 nM) in THP-1 cells. Whereas compared with baricitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations (≤ 100 nM). All JAKi inhibited GM-CSF-induced IL-1β production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1β production were larger compared to those of tofacitinib or upadacitinib at lower concentrations (≤ 100 nM). Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils. Conclusion We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells. Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi in the inhibition of JAK2 signaling pathways.

Published
2020

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